Researchers discover mechanism for multiplying adult stem cells

While the field of human embryonic stem cell research receives a tremendous amount of public attention, many scientists are also exploring the potential of adult stem cells for possible therapies. But this field raises other difficulties. Although adult stem cell research isn’t fraught with the controversies that surround embryonic stem cells, adult stem cells are extremely difficult to isolate and then to multiply in a lab dish. Now, as reported in the May 6 issue of the journal Cell, researchers in the lab of Whitehead Institute Member Rudolf Jaenisch have discovered a mechanism that might enable scientists to multiply adult stem cells quickly and efficiently.

“These findings provide us with a new way of looking at adult stem cells and for possibly exploiting their therapeutic potential,” says Jaenisch, who also is a professor of biology at MIT. This research focuses on a gene called Oct4, a molecule that is known to be active in the early embryonic stage of an organism. Oct4’s primary function is to keep an embryo in an immature state. It acts as a gatekeeper, preventing the cells in the embryo from differentiating into tissue-specific cells. While Oct4 is operating, all the cells in the embryo remain identical, but when Oct4 shuts off, the cells begin growing into, say, heart or liver tissue.

Konrad Hochedlinger, a post-doctoral researcher in Jaenisch’s lab, was experimenting with the Oct4 gene, curious to see what happens in laboratory mice when the gene is reactivated in adult tissue where it has long been dormant. Hochedlinger found that when he switched the gene on, the mice immediately formed tumors in the gut and in the skin where the gene was active. When he switched the gene off, the tumors subsided, demonstrating that the process is reversible.

Discovering that simply flipping a single gene on and off has such an immediate effect on a tumor was unexpected, even though Oct4 is known to be active in certain forms of testicular and ovarian cancer. Still, the most provocative finding was that “Oct4 causes tumors by preventing adult stem cells in these tissues from differentiating,” says Hochedlinger. In other words, with Oct4 active, the stem cells could replicate themselves indefinitely, but could not produce mature tissue.

One of the main obstacles with adult stem cell research is that, in order for these cells to be therapeutically useful, researchers need to multiply them in the lab. But when adult stem cells are isolated, they immediately start growing into their designated tissue type. It would be ideal if scientists had a way to take a liver adult stem cell and multiply it in a dish without having it form mature liver tissue.

This experiment showed that when Oct4 was reactivated, the adult stem cells in those tissues continued to replicate without forming mature tissue. In a mammal’s body, this type of cell behavior causes tumors. But under the right laboratory conditions, it could be a powerful tool. “This may allow you to expand adult stem cells for therapy,” observes Hochedlinger. “For instance, you could remove a person’s skin tissue, put it in a dish, isolate the skin stem cells, then subject it to an environment that activates Oct4. This would cause the cells to multiply yet remain in their stem cell state. And because this process is reversible, after you have a critical mass of these cells, you can then place them back into the person where they would grow into healthy tissue.” “This could be very beneficial for burn victims,” Jaenisch adds.

Researchers in his lab are also exploring whether activating Oct4 in somatic cells, such as skin cells, would make it easier for these cells to be reprogrammed when used as donors for nuclear transplantation. If so, it may help scientists more efficiently “customize” embryonic stem cells that could be used to treat diseases such as diabetes or Parkinson’s.